Introduction: Assessment of interactions among antiepileptic drugs (AEDs) during polytherapy is still a challenging issue for physicians and epileptologists worldwide. In spite of 25 currently licensed AEDs, there are no algorithms allowing a proper choice of these drugs to create combinations which would offer epileptic patients an efficacious therapy in the case of seizures refractory to monotherapeutic use of the AEDs. To characterize a type of interaction for a three-drug mixture of oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM) in an experimental model of tonic-clonic seizures, an isobolographic analysis of interaction was applied. Material and methods: The anticonvulsant effects of the three-drug mixture of OXC, PGB and TPM with respect to suppression of tonic-clonic seizures in mice were assessed in the mouse maximal electroshock-induced seizure model. Type I isobolographic analysis was used to characterize the type of interactions among three AEDs. Potential acute adverse effects were evaluated in the chimney, passive avoidance and grip-strength tests. Results: The three-drug mixture of OXC, PGB and TPM exerted supra-additive (synergistic) interaction in the mouse maximal electroshock-induced seizure model. The combination of OXC, PGB and TPM did not produce any acute adverse effects in mice in the chimney, passive avoidance and grip-strength tests. Conclusions: The isobolographic synergy observed experimentally for the combination of OXC, PGB and TPM could be recommended to patients with drug-resistant epilepsy, if the results of this study were translated to clinical settings.